Marjorie J. Arca

Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease

Purpose: We report a male child who presented at 15 months with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistulae, consistent with a Crohn disease-like illness. The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management.Methods: We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management.Results: After sequencing, we identified 16,124 variants. Subsequent analysis identified a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene, substituting a tyrosine for a highly conserved and functionally important cysteine. X-linked inhibitor of apoptosis was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD signaling pathway. The mutation was confirmed by Sanger sequencing in a licensed clinical laboratory. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 ligands, consistent with loss of normal X-linked inhibitor of apoptosis protein function in apoptosis and NOD2 signaling.Conclusions: Based on this medical history, genetic and functional data, the child was diagnosed as having an X-linked inhibitor of apoptosis deficiency. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At >42 days posttransplant, the child was able to eat and drink, and there has been no recurrence of gastrointestinal disease, suggesting this mutation also drove the gastrointestinal disease. This report describes the identification of a novel cause of inflammatory bowel disease. Equally importantly, it demonstrates the power of exome sequencing to render a molecular diagnosis in an individual patient in the setting of a novel disease, after all standard diagnoses were exhausted, and illustrates how this technology can be used in a clinical setting.

Laparoscopic adrenalectomy for cancer.

We will review the literature on the operative techniques and patient outcomes of laparoscopic adrenalectomy for cancer. Further, in our own study, an analysis of the preoperative assessment, operative, and hospital course, and postoperative follow-up was performed on all patients undergoing a laparoscopic adrenalectomy for cancer or metastasis from October 1996 through February 1998. Twelve laparoscopic resections were performed in 11 patients. There were six males and five females with an average age of 62 years (range, 40 to 79). The mean American Society of Anesthesiologists (ASA) score was 3.1 (range, 2 to 4). All of the tumors except one were due to metastatic cancer. The metastatic sources included renal cell cancer (four), lung cancer (two), colon cancer (two), adrenal cancer (one), and melanoma (one). Seven patients required a left adrenalectomy, three underwent a right adrenalectomy, and one was bilateral. The approach was transperitoneal in eight cases and retroperitoneal in four. The mean size of the tumors was 5.9 cm (range, 1.8 to 12 cm). Operative time averaged 181 minutes (range, 100 to 315 minutes), and blood loss was 138 cc (range, 20 to 1,300 cc). Average hospital stay was 2.3 days (range, < 1 to 6 days). One patient required conversion to an open approach due to local invasion of the tumor into the lateral wall of the vena cava, which was resected with the specimen. This procedure resulted in the largest blood loss of the series (1,300 cc). All specimens had negative surgical margins. There was one complication (9%), a laceration of the epigastric artery, which was controlled laparoscopically. At a mean follow-up of 8.3 months (range, 0.5 to 19 months), there have been no port site or local recurrences. One patient has developed a new hepatic nodule, which is being worked up for metastatic disease. Ten of the 11 patients (91%) are currently alive; one has died of expansive cerebral metastases from melanoma.

Clinical manifestations of appendiceal pinworms in children: an institutional experience and a review of the literature

The association of Enterobius vermicularis infestation with acute appendicitis varies from 0.2–41.8% worldwide. Our purpose was to determine the significance of Enterobius-associated appendicitis by retrospective review of appendectomies performed during a 5-year period at a major children’s hospital. The Surgical Pathology database at Children’s Hospital, Columbus, Ohio, was reviewed for appendiceal specimens found to have Enterobius infestation. Corresponding patient charts were evaluated for age, gender, presenting symptoms, laboratory data, operative findings, and clinical course. Of the 1,549 appendectomies performed from January 1998 through January 2003, 21 specimens (1.4%) were found to contain Enterobius vermicularis. Fifteen of the appendectomies were performed for symptoms of acute appendicitis; the remaining six were incidental appendectomies in conjunction with other operations. The mean age was 8.9 years. Ten patients were male; 11 were female. Of the 15 symptomatic children, nine presented with fever >99.0ºF, and 11 had a WBC count >10,000. Intra-operative appearance of the appendix ranged from normal to perforation. Pathologic evaluation showed neutrophil or eosinophil infiltration in 15 of the 21 specimens. Enterobius infestation is an uncommon cause of acute appendicitis in children in the United States. It may be associated with acute appendicitis, “chronic appendicitis,” ruptured appendicitis, or with no significant clinical symptoms.

Parenteral nutrition–associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review

OBJECTIVE The aim of this study was to review evidence-based data addressing key clinical questions regarding parenteral nutrition-associated cholestasis (PNAC) and parenteral nutrition-associated liver disease (PNALD) in children. DATA SOURCE Data were obtained from PubMed, Medicine databases of the English literature (up to October 2010), and the Cochrane Database of Systematic Reviews. STUDY SELECTION The review of PNAC/PNALD has been divided into 4 areas to simplify ones understanding of the current knowledge regarding the pathogenesis and treatment of this disease: (1) nonnutrient risk factors associated with PNAC, (2) PNAC and lipid emulsions, (3) nutritional (nonlipid) considerations in the prevention of PNAC, and (4) supplemental medications in the prevention and treatment of PNAC. RESULTS The data for each topic area relevant to the clinical practice of pediatric surgery were reviewed, evaluated, graded, and summarized. CONCLUSIONS Although the conditions of PNAC and PNALD have been well recognized for more than 30 years, only a few concrete associations and treatment protocols have been established.

A timely arrival for genomic medicine

In this issue of GIM,1 we describe a young boy who presented with unusually aggressive inflammatory bowel disease refractory to medical and surgical treatment. To reach a diagnosis, we were compelled to use genomic technology that, at the time, was not a clinically validated test. This case stimulated many discussions within our group and institution on the boundary between research and clinical care. Many of the same issues were raised again during review of the manuscript, further shaping our thinking about how this case speaks to the broader issue of genomics in medical practice. The purpose of this commentary is to expound on these issues, hopefully to stimulate discussion within the wider medical community. CLINICAL COURSE AND THE DECISION TO SEQUENCE Our article1 provides an abbreviated history of this patient’s unusual clinical course. In this limited space, it is difficult to convey the profound disability and suffering the child endured through numerous long hospital stays, and the resulting frustration that we experienced as we struggled to control the disease. Over a 3-year period, there were more than 100 surgical procedures, clinical consultations with physicians from around the world, innumerable informal discussions, weekly clinical care meetings, and informal e-mail consultations with world-leading experts. Despite these measures, we enjoyed little strategic success. Allogeneic hematopoietic progenitor cell transplant was regularly brought up as a potential therapy, but two main barriers prevented us from moving forward. First, for the majority of the clinical course, the child was judged to be too ill to have a reasonable chance of surviving the first 100 days of the transplant process. Second, we lacked a firm diagnosis; hence, we could not predict whether bone marrow transplant would be likely to help. However, the risks of morbidity and mortality were high. Although the disease could be intermittently brought into remission, it was felt that eventually the child would succumb to drug toxicity, total parenteral nutrition liver disease, or recurrence. Thus, from a therapeutic standpoint, we were left with no viable long-term options. The disease shared some similarities with Crohn disease, but the severity and tempo of disease progression was highly atypical. Exhaustive efforts to reach a diagnosis revealed numerous abnormalities in this child’s immune system, but none of these were pathognomonic for a specific disease. Similarly, conventional genetic testing of numerous candidate genes had failed to reach an answer. Therefore, we decided the next logical step was to sequence the patient’s exome (all known exons within the patient’s genome). FROM DATA TO DIAGNOSIS Initially, we formulated the following hypothesis: the disease was likely to be a single gene disorder with a recessive mode of inheritance. As we were looking for a recessive disease with a population frequency of 1:10,000, we could exclude genetic variants found in more than 1% of the general population as being causal of the child’s disease. Initial analysis was limited to a set of 2006 target genes to reduce the risk of discovering off target information. After it was clear that none of the candidate genes harbored a pathogenic mutation, we broadened the analysis to include all known genes, eventually leading to the identification of a mutation in the XIAP gene. Because XIAP deficiency was not previously known to cause a severe Crohn-like phenotype, we then confirmed the loss of XIAP protein function in the patient’s cells. Having diagnosed the patient with XIAP deficiency, we needed to reorient the clinical approach to address the attendant risks of hemophagocytic lymphohistiocytosis (HLH), regardless of its role in the etiology of the patients inflammatory bowel disease. 2 Accordingly, we evaluated for Epstein-Barr Virus infection (negative to date) and considered approaches to chemoprophylaxis. We reviewed the intestinal pathology and bone marrow specimens, performed a liver biopsy, and established that there was no evidence of active HLH. Nevertheless, the data regarding the natural history of XLP2 suggest that this child had a high probability of death due to HLH in the future, an outcome that could be prevented by hematopoietic stem cell transplant. Therefore, this was the singular basis for the decision to perform a transplant. Furthermore, the link between XIAP and a loss of NOD2 signaling, a pathway implicated in Crohn disease, gave us hope that a transplant could improve the gastrointestinal condition as well.

Treatment of necrotizing enterocolitis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review

OBJECTIVE The optimal treatment of necrotizing enterocolitis (NEC) is a common challenge for pediatric surgeons. Although many studies have evaluated prevention and medical therapy for NEC, few guidelines for surgical care exist. The aim of this systematic review is to review and evaluate the currently available evidence for the surgical care of patients with NEC. METHODS Data were compiled from a search of PubMed, OVID, the Cochrane Library database, and Web of Science from January 1985 until December 2011. Publications were screened, and their references were hand-searched to identify additional studies. Clinicaltrials.gov was also searched to identify ongoing or unpublished trials. The American Pediatric Surgical Association Outcomes and Clinical Trials Committee proposed six questions deemed pertinent to the surgical treatment of NEC. Recent Cochrane Reviews examined three of these topics; a literature review was performed to address the additional three specific questions. RESULTS The Cochrane Reviews support the use of prophylactic probiotics in preterm infants less than 2500 grams to reduce the incidence of NEC, as well as the use of human breast milk rather than formula when possible. There is no clear evidence to support delayed initiation or slow advancement of feeds. For surgical treatment of NEC with perforation, there is no clear support of peritoneal drainage versus laparotomy. Similarly, there is a lack of evidence comparing enterostomy versus primary anastomosis after resection at laparotomy. There are little data to determine the length of treatment with antibiotics to prevent recurrence of NEC. CONCLUSION Based on available evidence, probiotics are advised to decrease the incidence of NEC, and human milk should be used when possible. The other reviewed questions are clinically relevant, but there is a lack of evidence-based data to support definitive recommendations. These areas of NEC treatment would benefit from future investigation.

Splenic artery aneurysms: Methods of laparoscopic repair

PURPOSE Surgical therapy for splenic artery aneurysms (SAAs) has traditionally consisted of a laparotomy with resection of the aneurysm and possibly a splenectomy. Our early experience with the laparoscopic approach to treat SAAs is reported. METHODS A retrospective review of medical records was conducted on all patients who underwent laparoscopic resection of SAAs at the Cleveland Clinic Foundation from May 1996 to August 1997. RESULTS Four patients with SAAs, three women and one man, with an average age of 55 years (range, 37 to 63 years), underwent successful laparoscopic SAA repair. The average size of the aneurysm was 3.2 cm (range, 2.5 to 5.0 cm). Three patients underwent an aneurysm resection, whereas one patient underwent simple ligation. Intraoperative ultrasound scanning with Doppler was used in three cases as a means of localizing the aneurysm and identifying all feeding vessels; the complete cessation of flow within the aneurysm in the case in which the feeding vessels were simply ligated was also documented. The average intraoperative time was 150 minutes (range, 100 to 190 minutes). The mean estimated blood loss was 105 mL (range, 20 to 300 mL). There were no intraoperative complications. The average hospital stay was 2.2 days (range, 1 to 4 days). CONCLUSION The laparoscopic approach to splenic artery aneurysm by aneurysmectomy or splenic artery ligation can be safe and effective. The laparoscopic approach affords a short hospital stay and an effective result.

The diagnosis and management of empyema in children: a comprehensive review from the APSA Outcomes and Clinical Trials Committee.

The aim of this study is to review the current evidence on the diagnosis and management of empyema. The American Pediatric Surgical Association Outcomes and Clinical Trials Committee compiled 8 questions to address. A comprehensive review was performed on each topic. Topics included the distinction between parapneumonic effusion and empyema, the optimal imaging modality in evaluating pleural space disease, when and how pleural fluid should be managed, the first treatment option and optimal timing in the management of empyema, the optimal chemical debridement agent for empyema, therapeutic options if chemical debridement fails, therapy for parenchymal abscess or necrotizing pneumonia and duration of antibiotic therapy after an intervention. The evidence was graded for each topic to provide grade of recommendation where appropriate.

Beyond feasibility: a comparison of newborns undergoing thoracoscopic and open repair of congenital diaphragmatic hernias

BACKGROUND Although both laparoscopic and thoracoscopic repair of congenital diaphragmatic hernia (CDH) have been described in the literature, neither appropriate selection criteria nor improved outcomes for minimally invasive repair over open repair have been clearly delineated. METHODS We reviewed our experience with neonatal CDH repair between 2004 and 2007 to determine clinical parameters that are associated with successful thoracoscopic CDH repair. We compared these patients to a similarly matched cohort of patients who had undergone an open neonatal CDH repair between 1999 and 2003. RESULTS From 2004 to 2007, 20 (61%) of 33 patients underwent successful neonatal thoracoscopic CDH repair. Characteristics common to all patients who underwent successful thoracoscopic repair included absence of congenital heart defects, no need for extracorporeal membrane oxygenation, ventilatory peak inspiratory pressure of less than 26 cmH(2)O, and oxygenation index less than 5 on the day of planned surgery. From 1999 to 2003, 40 patients underwent an open neonatal CDH repair, of which 18 (45%) patients would have matched our selection criteria for thoracoscopic repair. These 2 cohorts were similar in age, estimated gestational age, weight, APGAR scores, and oxygenation index at the time of surgery. The thoracoscopic cohort had statistically and clinically significant quicker return to full enteral feeds, had shorter duration on the ventilator postoperatively, and required less narcotic/sedation postoperatively. Less severe complications occurred in the thoracoscopic cohort. Adjusted total hospital charges were less for the thoracoscopic repair. CONCLUSIONS Successful thoracoscopic CDH repair can be expected in newborns, which has limited respiratory compromise. Thoracoscopic CDH repair is associated with lower morbidity and quicker recovery than traditional open repair and without increased risk of recurrence or complications.

Laparoscopic repair of lumbar hernias

BACKGROUND Lumbar hernias are rare defects in the posterolateral abdominal wall that may be congenital or acquired. Repairing these defects is difficult by virtue of their location and the inherent weakness of the surrounding tissues. We report a series of seven patients who had their lumbar hernias repaired laparoscopically at two institutions. STUDY DESIGN We retrospectively reviewed all lumbar hernias repaired laparoscopically in our institutions within the last 16 months (August 1996 to November 1997). Postoperative followup was 1-15 months. RESULTS Seven patients underwent laparoscopic repair. Five hernias were acquired defects and two were congenital. One to three defects were found per patient. The average size of the hernia defect was 77.8 cm2. We used a polypropylene or a polytetrafluoroethylene mesh in all patients; the average size of the mesh used was 336.4 cm2. The average length of hospital stay was 1.7 days. One patient returned with an abscess over the mesh, which necessitated removal of the graft. Otherwise, there were no complications, and the remaining six patients had no recurrences after followup of 1-14 months. CONCLUSIONS The laparoscopic approach is safe and effective for repairing lumbar hernias. Advantages of this approach include excellent operative visualization, decreased hospital stay postoperatively, and a solid repair without recurrence during shortterm followup.